Protein/polymer Devices for Slow-release of Immunotherapies to Treat Ovarian Cancer Summary Ovarian cancer is the leading cause of death amongst gynecologic diseases, with over 100,000 deaths per year worldwide. Prognosis is poor, because patients often present with disseminated disease. We propose an immunotherapy approach using a virus-like particle (VLP) technology and in situ vaccination. Using soluble VLPs and weekly treatment sessions, we have achieved potent efficacy in a hyper-aggressive mouse model of ovarian cancer (ID8vegf/defb29 cells and C57BL6 mice) with 50% animals being cured from the disease. To alleviate the need for repeated treatment sessions and to further increase potency of the approach, we propose to formulate VLPs into a slow-release vaccine delivery device using melt-based polymer processing methods. The clinical utility of such a device would be immense. Ovarian cancer is typically treated by surgical debulking followed by an aggressive regimen of chemotherapy. The PIs envision a simple modification to the treatment work-flow, where a small degradable implant is left in the IP cavity, releasing the in situ vaccine over the course of weeks-to-months. Such a device would eliminate repeated and painful IP injections and lead to enhanced efficacy due to depot effects related to immune priming. A strong set of preliminary data indicate feasibility of the approach: we demonstrate stability of VLP/polymer blends manufactured through melt-based extrusion. Data indicate that VLPs retain their macromolecular structure after melt-based processing into a slowly-degrading poly(lactic-co-glycolic acid) (PLGA) polymer. The manufacturing technique is critically important to incorporate sufficient amounts of VLP therapeutic into an implantable device; 100% of the active therapeutic is incorporated in melt-processing, where up to 70% can be lost during solvent-based encapsulation. Furthermore, the manufacturing process is universally accepted in industry, making the device highly translatable. The innovation within our team lies in coupling the in situ vaccination technology with polymer device manufacturing to enable a next-generation treatment of ovarian cancer. VLP/polymer blends will be developed through melt-extrusion processing; the engineering space is vast and will be defined within this proposal by vaccine loading levels ranging from 1-25% VLP/PLGA (w/w%) and manipulation of formulation components to tune release rates from weeks to months. The efficacy of the vaccine devices will be evaluated using mouse models of ovarian cancer. We will determine the anti-tumor efficacy and immune priming capabilities comparing soluble VLP vs. VLP devices. The fate of soluble vs. released VLP will be determined through non-invasive imaging coupled to immunological analysis to gain insights into the underlying mechanism of the stimulated anti-tumor immune response. In summary, the PIs propose a disruptive treatment formulation for metastatic ovarian cancer. The multiple-PI leadership team brings complementary expertise in polymer/protein blends and VLP-based in situ vaccination, and are thus uniquely poised to execute the research.